Inflammatory Bowel Diseases (IBD) is a group of inflammatory conditions of the colon and small intestine. The main forms of IBD are Crohn's disease (CD) and Ulcerative Colitis (UC). Other forms of IBD, which are not always classified as typical IBD and which include far fewer cases are Collagenous colitis, Lymphocytic colitis, Ischaemic colitis, Diversion colitis, Behçet's disease, and Indeterminate colitis. The main difference between crohn's disease and UC is the location and nature of the inflammatory changes. Crohn's disease can affect any part of the gastrointestinal tract, from mouth to anus, although a majority of the cases start in the terminal ileum. UC, in contrast, is restricted to the colon and the rectum. Microscopically, UC is restricted to the mucosa (epithelial lining of the gut), while crohn's disease affects the whole bowel wall (transmural lesions). Finally, crohn's disease and UC present extra-intestinal manifestations (such as liver complications, arthritis, skin manifestations and eye complications) in different proportions.
Semaphorins are a family of membrane bound and soluble proteins classified into eight sub-classes based on their structural domains Semaphorins mainly regulate focal adhesion assembly/disassembly and induce cytoskeletal remodeling, thus affecting cell shape, cell attachment to the extracellular matrix, cell motility, and cell migration. Although Semaphorins were originally identified as affecting axon guidance during development of the nervous system, they are now thought to fulfill diverse physiological roles including organogenesis, vascularization, angiogenesis, neuronal apoptosis, and neoplastic transformation. Additionally, recent studies pointed to the involvement of Neuropilin-1 (a receptor for semaphorin 3) and certain Semaphorins in the regulation of the immune system, and thus these Semaphorins are denoted “immune Semaphorins”.
The seven class-3 Semaphorins (Semaphorin 3s), designated by the letters A-G, are the only vertebrate secreted Semaphorins. Neuropilins (Nrps) and the type A/D family Plexins (Plexin-A1, -A2, and -A3, and Plexin-D1) act as receptors for Semaphorin 3. Each Semaphorin 3 family member shows distinct binding preference for Nrps. Each Sema3-Nrp complex associates with specific plexins to mediate downstream signaling. Most membrane-bound vertebrate Semaphorins directly bind plexins, while class-3 Semaphorins require Neuropilins as obligate co-receptors.
Semaphorin 3A (Sema3A), a class-3 secreted member of the Semaphorin family, has been established as an axonal guidance factor during development. Interestingly, several lines of evidence suggest that Sema3A also affects immune cell functions. Sema3A has been shown to be expressed by activated T cells and inhibit T cell proliferation and cytokine secretion (Catalano, A et al, 2006, Blood 107: 3321-3329; Lepelletier, Y. et al., 2006, Eur. J. Immunol. 36: 1782-1793). Moreover, the expression of Sema3A, Neuropilin 1 (NP-1), Neuropilin 2 (NP-2), and Plexins was found to be increased on differentiating macrophages and on activated T cells (Ji J D et al., 2009, Human Immunol., 70(4): 211-7). Additionally, Neuropilin-1 expression on regulatory T cells has been shown to enhance interactions with immature dendritic cells (DCs) during antigen recognition, resulting in higher sensitivity to limiting amounts of antigen.
One study has shown that overexpression of Sema3A in a mouse model of collagen-induced arthritis resulted in reduced incidence, disease severity, and articular inflammation. Moreover, in line with results in arthritic mice, the study showed a defective Sema3A expression in CD4+ T cells derived from patients with rheumatoid arthritis (Catalano A. et al., 2010, J. Immunol., 185: 6373-83).
In another study, kidney biopsies from lupus glomerulonephritis (LGN) patients showed stronger staining with anti-NP-1, and anti-Semaphorin 3A antibodies as compared with either normal biopsies or biopsies from patients with primary nephropathy and proteinuria (Vadasz Z. et al., 2011, Lupus, 20:1466-1473). A subsequent study has shown that Sema 3A serum levels in SLE patients are significantly lower than in healthy individuals (Vadasz Z. et al, 2012, Arthritis Research & Therapy, 14:R146).
U.S. Application Publication No. 2012/0251539 discloses a method of treating an immune-related disorder in a subject, comprising administering to the subject an effective amount of a Sema3A inhibitor, resulting in reduced Sema3A activity in the subject.
International Patent Application, publication No. WO 2014/199364 to inventors of the present invention, discloses Semaphorin 3A and its use in the treatment and prognosis of Systemic Lupus Erythematosus (SLE).
US Patent Application, publication No. 2015/0216929 to inventors of the present invention, discloses Semaphorin 3A and its use in the treatment of Asthma and in assessing Asthma severity and treatment efficacy.
In yet another study, it has been shown that administration of Sema3A alleviates sneezing and nasal rubbing in a murine model of Allergic Rhinitis (Sawaki H. et al., 2011, J. Pharmacol. Sci., 117(1): 34-44).
There is an unmet need, for safe and effective approaches to treat IBD. There is also a need for reliable biomarkers with which treatment efficacy and disease condition and/or severity could be assessed.